Cutting Edge: Small Molecule CD40 Ligand Mimetics Promote Control of Parasitemia and Enhance T Cells Producing IFN-γ during Experimental<i>Trypanosoma cruzi</i>Infection

Habib, M.; Rivas, Magali Noval; Chamekh, Mustapha; Wieckowski, Sébastien; Sun, Weimin; Bianco, Alberto; Trouche, Nathalie; Chaloin, Olivier; Dumortier, Hélène; Goldman, Michel; Guichard, Gilles; Fournel, Sylvie; Vray, Bernard

doi:10.4049/jimmunol.178.11.6700

Cited by 23 publications

(25 citation statements)

References 20 publications

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“…Recent evidence suggests that treatment of mice with CD154 mimetics enhances the immune response to T cruzi, promoting parasite clearance and decreasing mortality. 42 Carriers of the G allele of rs11086998 may have a similar enhanced immune response to T cruzi infection and be less likely to develop complications of chronic Chagas disease, which can involve the cardiac, nervous, and digestive systems. 42 Future experiments in an hCD40P227A transgenic mouse will test this possibility.…”

Section: Discussionmentioning

confidence: 99%

A novel polymorphism of the human CD40 receptor with enhanced function

Peters

Plenge

Graham

et al. 2008

Blood

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CD40 signaling is critical for innate and adaptive immunity against pathogens, and the cytoplasmic domain of CD40 is highly conserved both within and between species. A novel missense single nucleotide polymorphism (SNP) in the cytoplasmic domain of CD40 at position 227 (P227A) was identified, which resides on a conserved ancestral haplotype highly enriched in persons of Mexican and South American descent. Functional studies indicated that signaling via human (h) CD40-P227A stably expressed in several B-cell lines led to increased phosphorylation of c-Jun, increased secretion of the pro-inflammatory cytokines interleukin (IL)-6 and TNF-, and increased Ig production, compared with wild-type hCD40. Cooperation between hCD40-P227A signaling and B-cell receptor (BCR)-or Toll-like receptor 9 (TLR9)-mediated signaling was also enhanced, resulting in elevated and syn-ergistic production of IL-6 and Ig. We have thus identified a novel genetic variant of hCD40 with a gain-of-function immune phenotype. (Blood. 2008;112: 1863-1871)

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Section: Discussionmentioning

confidence: 99%

A novel polymorphism of the human CD40 receptor with enhanced function

Peters

Plenge

Graham

et al. 2008

Blood

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“…For example in monkey models of HIV [4] and in hepatitis C virus (HCV) infection [5], the virus doubles only every 10 h. In hepatitis B virus (HBV) infection, growth is even slower because the virus doubles as slowly as every 2-3 days [6,7]. Growth of tuberculosis (TB) and trypanosomes is similarly slow, with doubling times of 28 h [8] and >18 h [9,10], respectively. Because these pathogens divide much more slowly than lymphocytes are able to, why does the immune system not just 'outrun' these pathogens?…”

Section: The Racementioning

confidence: 99%

The race between infection and immunity: how do pathogens set the pace?

Davenport

Belz

Ribeiro

2009

Trends in Immunology

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“…Peripheral blood mononuclear cells (PBMC) from X-HIM patients also secrete markedly lower amounts of IFN-γ and IL-12 in response to T. gondii [16]. CD40L knockout ( - / - ) mice are more susceptible to L. major infection [17], while mice treated with molecules that bind CD40, thereby mimicking the effects of soluble CD40L, exhibit a decreased severity of experimental L. major or T. cruzi infection [17,18]. The CD40-CD40L signaling pathway also is involved in matrix metalloproteinases (MMPs) expression, including MMP-9 [19,20].…”

Section: Introductionmentioning

confidence: 99%

High levels of soluble CD40 ligand and matrix metalloproteinase-9 in serum are associated with favorable clinical evolution in human visceral leishmaniasis

et al. 2013

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BackgroundSoluble CD40 ligand (sCD40L) and matrix metalloproteinase 9 (MMP-9) are inflammation markers and have been poorly described in infectious disease. In this prospective study, we describe the sera kinetics of these two molecules in the course of treatment follow up in human visceral leishmaniasis (VL).MethodsSera from VL patients were collected before and during follow up of regular Antimony treatment. sCD40L and MMP-9 were measured by Luminex assay. Paired analysis by Wilcoxon signed test was used for comparison of values of the same subjects before and after initiation of treatment. Correlations between clinical data and parasite load with the serum levels of sCD40L and MMP-9 were performed by Spearman test. Tests were considered statistically significant if the probability of a type I error was less than 5% (p-value < 0.05).ResultsWhile sCD40L and MMP-9 were not observed in sera from non endemic controls which are at low risk of Leishmania chagasi infection, elevated levels were observed in sera from VL patients, and an increase in sCD40L and MMP-9 levels were detectable during the follow-up of VL patients undergoing antimony treatment. sCD40L levels were also high in individuals living in endemic settings at high risk of infection (endemic controls). Additionally, negative correlations were found between spleen sizes and MMP-9 before treatment and sCD40L at day 15 of treatment. Negative correlations were also found between parasite load with both sCD40L and MMP-9.ConclusionSerum sCD40L and MMP-9 are identified as new and simple biomarkers in two situations: (i) monitoring the success of therapy and (ii) predicting favorable clinical outcome of human VL.

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Cutting Edge: Small Molecule CD40 Ligand Mimetics Promote Control of Parasitemia and Enhance T Cells Producing IFN-γ during ExperimentalTrypanosoma cruziInfection

Cited by 23 publications

References 20 publications

A novel polymorphism of the human CD40 receptor with enhanced function

A novel polymorphism of the human CD40 receptor with enhanced function

The race between infection and immunity: how do pathogens set the pace?

High levels of soluble CD40 ligand and matrix metalloproteinase-9 in serum are associated with favorable clinical evolution in human visceral leishmaniasis

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